1. Field of the Invention
This invention relates to a device and a method for obtaining interstitial fluid from the body of a patient for use in a diagnostic test. More particularly, this invention relates to a device and a method for obtaining interstitial fluid from the body of a patient at a rapid rate of collection.
2. Discussion of the Art
Interstitial fluid is the substantially clear, substantially colorless fluid found in the human body that occupies the space between the cells of the human body. Several methods have been used to obtain interstitial fluid from the body of a patient for diagnostic tests. Diagnostic tests that can be run with samples of interstitial fluid include, but are not limited to, glucose, creatinine, BUN, uric acid, magnesium, chloride, potassium, lactate, sodium, oxygen, carbon dioxide, triglyceride, and cholesterol.
It is much more difficult to obtain a sample of interstitial fluid from the body of a patient than it is to obtain a sample of blood from the body of a patient. Blood is pumped under pressure through blood vessels by the heart. Consequently, a cut in a blood vessel will naturally lead to blood flowing out of the cut because the blood is flowing under pressure. Interstitial fluid, which is not pumped through vessels in the body, is under a slight negative pressure. Moreover, the amount of interstitial fluid that can be obtained from a patient is small because this fluid only occupies the space between the cells of the human body. Currently available methods for obtaining large amounts of interstitial fluid are unsatisfactory, because these methods are accompanied by undesirable side effects.
Several methods have been employed to obtain access to interstitial fluid for glucose monitoring. These methods include, but are not limited to, microdialysis, heat poration, open flow microperfusion, ultrafiltration, subcutaneous implantation of a sensor, needle extraction, reverse iontophoresis, suction effusion, and ultrasound.
Microdialysis involves placing microdialysis tubes in the body, introducing a fluid into the tubes, allowing the fluid to traverse the length of tubing in the body, and withdrawing the fluid to a location outside the body. As the fluid passes through the microdialysis tubing in the body, glucose from the body is exchanged with the fluid inside the tubing, resulting in a change in glucose concentration primarily in the fluid inside the tubing. The change in the concentration of glucose in the tubing can be measured with a sensor that is external to the body.
There are several drawbacks in the use of microdialysis equipment for measuring the concentration of glucose. Microdialysis tubes have walls. The walls of the microdialysis tubes are formed from a material called dialysis membrane. This membrane allows molecules below a certain size to pass but restricts the movement of larger molecules. The amount of glucose that is exchanged may be small, leading to small changes in the concentration of glucose in the fluid inside the microdialysis tubing. These small changes in the concentration of glucose can be difficult to detect accurately. Moreover, the amount of time required for the fluid to circulate through the microdialysis tubes can be great. Accordingly, the concentration of glucose being measured by a sensor that is external to the body can lag behind the actual concentration of glucose inside the body by several minutes. Reducing the length of the tubing and increasing the rate of the pumping of the fluid can decrease the duration of this lag, but such actions also decrease the amount of glucose being transferred to the tubing. In addition, obtaining accurate measurements of the concentration of glucose from solutions having a low concentration of glucose is difficult. Furthermore, the microdialysis tubing can break off during use or upon withdrawal from the body, thereby presenting a hazard to the user. Finally, the exchange of glucose across the membrane of the tubing can vary over time, resulting in erroneous determinations of the concentration of glucose.
Heat generated by a light from a laser that acts upon a dye or heat generated by a heated wire can be used to form openings in the outermost layer of the skin, the stratum corneum. The formation of openings in the skin by means of heat is described in WO 97/07734. Interstitial fluid can be extracted from the openings in the skin by means of a vacuum or by application of pressure around the periphery of the openings. The use of a laser to form openings in the skin is expensive, because the laser must not only be powerful enough to cause the formation of the openings in the skin, but must also be properly focused to create small openings in the skin. A plurality of openings must be formed in the skin order to obtain a sufficient quantity of interstitial fluid. If one laser is used, the mechanism housing the laser will be complex and costly, on account of the necessity of additional components for moving the laser to a plurality of locations on the stratum corneum. Alternatively, a plurality of lasers could be incorporated into an instrument to form a plurality of openings in the stratum corneum. This approach would be costly because of the additional cost of extra lasers. Because of the limitations of the laser and because of unsightly discoloration caused by the formation of openings in the skin, the number of openings per each interstitial fluid extraction operation is typically limited to three to six. The amount of interstitial fluid extracted will be limited to the amount that can be drawn through these openings. A greater number of openings could provide an increased rate of collection of interstitial fluid, but a greater number of openings would be impractical. The openings would have to be distributed over a wide area of skin, thereby making the harvesting of the interstitial fluid difficult.
Open flow microperfusion is similar to microdialysis. A fluid flows through a tube placed in the body, and the fluid is exchanged between the body and the tube. The concentration of glucose in the fluid exiting the body is proportional to the concentration of glucose in the body. Typically, if the concentration of glucose in the fluid inside the tube is initially zero, by the time the fluid leaves the body, the concentration of glucose in the exiting fluid will be one-third that of the concentration of glucose in the body. The difference between open flow microperfusion and microdialysis resides in the type of tube used. Microdialysis tubes have very small pores that are designed to allow only small molecules to diffuse through the walls of the tube. Pore sizes in microdialysis tubing are typically on the order of 1 to 10 nm. Open flow microperfusion systems have pores typically on the order of 200 micrometers. In the case of open flow microperfusion, the pores should not restrict the movement of any molecules in the interstitial space. Neither the microdialysis method nor the open flow microperfusion method extracts a pure sample of interstitial fluid; accordingly, these methods require a calibration factor.
Ultrafiltration involves placing microdialysis tubing inside the body and extracting interstitial fluid from the body through the tubing by means of vacuum. A steady stream of fluid cannot be obtained because the application of vacuum leads to the formation of bubbles in the fluid. A lower level of vacuum would reduce bubble formation but would increase the amount of time required to remove the sample of interstitial fluid from the body and transfer it to a glucose detector. The pores of the microdialysis tubing become clogged over time, thereby leading to lower flow rates or the need to increase levels of vacuum. The interstitial fluid that is obtained does have concentrations of glucose similar to that found in blood, making the determination of the concentration of glucose more accurate than that of microdialysis. However, the length of tubing that must be inserted under the skin is typically on the order of centimeters in length. A typical patient cannot easily insert this length of tubing. Furthermore, the greater the length of the tubing, the more likely that it will break off during use or upon withdrawal from the body.
A sensor implanted beneath the skin can be used to monitor the concentration of glucose continuously. This type of sensor does not require removal of fluid from the body to measure the concentration of glucose. The sensor is difficult to calibrate because it is located inside the body. The only way to confirm the accuracy of the sensor is to measure blood glucose level by fingerstick methods. Furthermore, the sensor is subject to the motion of the body as well as to attacks by the body""s immune system. The overall accuracy of these devices is usually poor.
A hollow needle can be placed in the dermis layer of the skin and used to extract interstitial fluid by means of vacuum or by means of pressure applied to the skin around the periphery of the needle. The amount of interstitial fluid withdrawn is usually very small, typically on the order of one microliter or less. Interstitial fluid can enter the needle only through the open end. If the needle is used for extended periods of time, it may cause irritation to the user. The level of vacuum required to obtain a steady flow of interstitial fluid may be high and bubble formation may be seen, similar to that seen in the case of ultrafiltration. If a low level of vacuum is used, the flow of interstitial fluid may be slow and the significant lag time may cause the concentration of glucose measured to differ significantly from the actual concentration of glucose.
Passing a small current through the skin has been used to drive drugs having low molecular weight through the skin. This process is known as iontophoresis. The passage of current can also cause ionic material from within the skin to be extracted from the body in a process called reverse iontophoresis. As the ionic materials move outside the body, they drag water with them as well as any non-ionic material dissolved in the water. By means of this technique, glucose can be removed from the body through the skin. However, the process is slow and the concentration of glucose extracted is low.
Suction effusion first employs adhesive tape to remove the outer layer of the skin. The tape must be applied to the skin several times, typically 20 to 100, until the outer layer of skin is removed. Once the outer layer of skin is removed, a vacuum is applied to suck interstitial fluid out through the area where the outer layer of skin was removed. Removing the outer layer of the skin is very time consuming, and the amount of interstitial fluid that can be sucked out by means of the vacuum is very small.
Ultrasound has been claimed to cause the skin to become more porous. After the skin is exposed to ultrasonic energy, interstitial fluid containing glucose may be extracted from the more porous skin by means of a vacuum. It has also been suggested that ultrasound can aid in the transport of fluid across the skin. The concentration of glucose in the extracted fluid can then be measured by means of a glucose detector. Experimental evidence does not show conclusively that ultrasound causes the skin to become more porous. The techniques described in the prior art either obtain very little interstitial fluid from the body or require extreme conditions, e.g., the application of very high vacuum levels, to extract the interstitial fluid. The techniques of the prior art also suffer from the shortcoming of extracting fluids containing low concentrations of glucose, which concentrations are difficult to measure accurately.
In view of the foregoing, it would be desirable to develop a technique for obtaining interstitial fluid from the body of a patient at a rapid rate of collection. It is desired that the technique provide a large amount of interstitial fluid, that the technique not be harmful to the patient, that the technique be of low cost, and that the technique provide a sample that produces accurate results.
In one aspect, this invention provides a device for obtaining a sample of interstitial fluid from a patient for use in monitoring the level of blood glucose in the patient. The device comprises a hollow tube having a wall, wherein the wall of the tube contains a multiplicity of pores.
The shape of the tube preferably corresponds to the shape of the device used to form the opening in the skin into which the tube is inserted. For example, if the device for forming the opening in the skin is cylindrical, such as, for example, a needle, the tube is preferably cylindrical in shape. The preferred shape of the tube is cylindrical. The shape of the tube determines the shapes of the openings at each end of the tube.
The tube should be of sufficient length so that a sufficient number of pores can be formed in the wall of the tube so the flow rate of the interstitial fluid would be equal to or greater than the flow rate required for using a commercially feasible assay. The tube should not be so long that an excessively long needle would be required to insert it, because the use of such a long needle would be painful to the patient.
The tube should be of sufficient diameter that the flow rate of interstitial fluid will be adequate for a commercially feasible assay. The diameter should not be so great that insertion of the needle required to form the opening in the skin for the tube will cause excessive pain to the patient. The smallest practical needle or lancet for forming an opening in the skin of a patient is 31 gauge. The outer diameter of a needle of 31 gauge is about 0.25 mm. Therefore, the inside diameter of the tube is preferably at least about 0.25 mm. The inside diameter of the tube is limited by the size of the largest needle or lancet that could comfortably be used to form the opening in the skin to insert the tube. A needle of 18 gauge (about 1.25 mm in diameter) is probably the largest needle that would be inserted into a patient. The inside diameter of the tube preferably does not exceed 1.25 mm.
The thickness of the wall of the tube should be sufficient to ensure mechanical stability. Typically, a wall thickness of from about 0.2 mm to about 0.5 mm is preferred. The outside diameter of the tube preferably does not exceed 2.25 mm. The outside diameter of the tube is preferably at least about 0.65 mm.
The size of the pores in the wall of the tube preferably exceeds the diameter of a red blood cell so that the pores will not be clogged by red blood cells. The maximum pore size is preferably less than the inside diameter of the tube in order to maintain the mechanical integrity of the tube. The number of pores will be based on the desired porosity of the tube and the size of the pores.
In another aspect, this invention provides an assembly for inserting the device into the skin of a patient. In still another aspect, this invention provides a method for employing the device of this invention for obtaining obtain interstitial fluid from the body of a patient.
The device of this invention can obtain interstitial fluid from the body of a patient at a rapid rate of collection. Moreover, the device can provide a large amount of interstitial fluid. In addition, the device and method for its use are not harmful to the patient. The device is inexpensive. Most importantly, the device helps to provide a sample that produces accurate results.